Cancer is a serious disease and the leading cause of human death. It may occur anywhere in the human body, and may be caused by various factors including environmental factor and genetic factor, etc. A large number of studies have been conducted to conquer cancer; however, cancer is an incurable disease that has not yet been conquered. Existing therapies against cancer include surgery, chemotherapy and radiotherapy, etc. Although advances in medicine have led to improved prognosis, there are many limitations related thereto, including normal cells being also adversely affected as well as cancer cells. In particular, most cancer therapies are currently implemented using surgical removal (surgery) or chemotherapy. In recent years, other therapies, which are based on a different concept from that of such existing therapies, have been studied, and particular interests are given to the studies which are intended to achieve effective treatment by selectively treating cancer tissues using an autoimmune system naturally present in the human body so as to minimize adverse effects.
It has been reported that cytotoxic T lymphocytes (CTLs), which directly target cancer cells, are important for effective treatment of cancer. To date, studies on anti-cancer treatment using T cell therapy have been attempted in a way that delivers, to T cells of a patient, either a T cell receptor (TCR) recognizing a specific antigen or a chimeric antigen receptor (CAR) in which an antibody's scFv portion recognizing an antigen is grafted to a CD3 signaling domain. Grafting of CAR to T cells allows to activate T cells to exert its anti-cancer effect with only recognition of a specific antigen by scFv regardless of signal transduction by an antigen presenting cell (APC), and also this is not limited to the HLA type, which, in turn, enables it to be used as an effective therapy. However, it has been developed largely as a therapeutic for hematologic cancers. In the case of solid cancers, CAR exhibited low therapeutic effects since an environment, which can suppress immunological actions, was created around cancer cells. Activation of T cells may induce the expression of a cytotoxic T-lymphocyte-associated protein-4 (CTLA-4), which binds to a ligand for regulatory T cell (Treg) that regulates the activity of activated T cells, and transduces an inhibitory signal into T cells, thereby leading to decreased activity of cancer-targeting T cells.
As used herein, the term “gene therapy” refers to a method of treating inherited or acquired genetic abnormalities, which are difficult to treat by conventional methods, using a genetic engineering method. Specifically, gene therapy includes administering genetic materials such as DNA and RNA into the human body to express therapeutic proteins or to inhibit the expression of specific proteins, thereby treating and preventing inherited or acquired genetic defects, viral diseases, or chronic diseases such as cancers or cardiovascular diseases. Gene therapy allows to fundamentally treat diseases by analyzing the cause of a disease on a genetic level, and thus is expected to not only overcome incurable diseases but also to be used as an alternative to conventional medical methods.
On the other hand, in recent years, studies have been conducted to develop a tissue-specific adenovirus for cancer therapy. As a typical example, a method using a trans-splicing ribozyme or the like is being developed.
Studies on the development of a tissue-specific adenovirus for cancer therapy using the trans-splicing ribozyme attracted interests by the revelation that the group I intron ribozyme from Tetrahymena thermophila can link two separately present transcripts to each other by a trans-splicing reaction, not only in vitro, but also in bacterial cells and even in human cells.
Specifically, this group I intron-based trans-splicing ribozyme can target a specific tissue- or disease-related gene transcript or a specific RNA that is specifically expressed only in diseased cells, thereby leading to reprogramming so that the RNA is repaired back to normal or the gene transcript is converted into a new therapeutic gene transcript. Thus, it is expected that the group I intron-based trans-splicing ribozyme can become a tissue or disease-specific and safe gene therapeutic technology. In addition, a trans-splicing ribozyme can multiply its therapeutic effects, because it allows a unusual RNA to be eliminated and, at the same time, expression of a desired therapeutic gene product to be induced, thereby achieving inhibition of a gene corresponding to a unusual RNA and induction of expression of a desired therapeutic gene.
Particularly, in recent studies, trans-splicing ribozymes have been developed, which target a gene capable of functioning specifically on cancer tissues such as human telomerase reverse transcriptase (hTERT); however, these ribozymes exhibit a high tissue specificity due to their combination with a tissue-specific promoter while exhibiting a very low expression efficiency. Thus, they still have a disadvantage to overcome in terms of the therapeutic efficiency.
In other words, gene therapy using a trans-splicing ribozyme has still been under continued research and development in order to improve the therapeutic efficiency.
On the other hand, many attempts have been made to achieve effective anti-cancer therapy using the existing immune system. By causing a T cell to express CAR which recognizes a specific antigen, a T cell directly attacking cancer cells has been developed without relying on APC. However, it has been developed largely as a therapeutic for hematologic cancers. In the case of solid cancers where an environment suppressing immunological actions is created around cancer tissue, it is known that CAR exhibits low therapeutic effects. In order to overcome this problem, attempts were made to maintain the activity of a T cell expressing CAR by inhibiting CLTA-4, which interferes with the activity of activated T cells, thereby achieving effective anti-cancer effects. However, according to previously reported studies, combined use of an anti-cancer drug and an antibody to CTLA-4 resulted in an overall inhibition of CTLA-4, thereby leading to low specificity and even adverse effects in terms of the anti-cancer effect.